Are there sex differences in corpus callosum pathology ?

 Neurons are brain cells whose most characteristic property is to rapidly transmit information over certain distances, which in the spinal cord, can reach as far as a meter.  The part of the neuron that carries the information over any distance is called the axon.   The axonal part of the neuron is often called the neuron fiber.   One of the major fiber systems in the human brain is the main commissure connecting the two hemispheres called the corpus callosum.   Estimates of the number of neurons contained in the human corpus callosum range from 200 to 800 million.  A careful electron microscopy study for the purpose of a neuron count in the corpus callosum has yet to be carried out in humans.  The corpus callosum,  like other neuronal systems of the brain,  starts developing late in prenatal development,  during the third trimester of pregnancy,  and undergoes exuberant overdevelopment followed by massive and rapid pruning.   In short,  it contains many more neurons at one (prenatal) stage of its development than at its (post-natal) maturity,   many of its neurons being required to retract and die.  This is a normal process of prenatal development called neuronal mortality.  The corpus callosum is easy to measure macroscopically (with a simple ruler) in a brain sliced down the middle from front to back,  for it measures about six centimeters in length and is about a centimeter large.  Many studies have been carried out to determine whether the corpus callosum of the human is sex-dimorphic,  both using brains of dead people, as well as using radiological images of living patients.   My reading of that extensive literature has led me to conclude that,  in the human adult,  if there exists any macroscopic sex difference in the corpus callosum,  it is only in relation to handedness  -left handed men having the largest callosi and right handed women having the smallest.   So I don't want to make a case for a basic sex difference here.   However, perhaps because its prenatal development is subject to very rapid changes during a brief period,  the corpus callosum is very sensitive to teratogens (substances which cause deformities in fetuses).   For example,  as has been extensively studied in rats (less so in humans) maternal consumption of alcohol during the second or third trimester can cause agenesis (failure to grow) of the corpus callosum,  and this affects male (pups) more than females.  The same effect is observed with prenatal exposure to cocaine.  This sex difference is rather well established in the animal literature, having now been consistently replicated. Furthermore,  in rat fetuses,  contrarily to humans,  there is a basic sex difference in callosal dimension.  Males have larger callosi. Electron microscopes have now been extensively used to investigate callosal neurons in rats.  Axon number calculations revealed no sex differences in total axon number. Males, however, have significantly more myelinated axons than females.  Hormonal masculinization of female rat fetuses results in development of a larger corpus callosum.   Even more interestingly,  hormonal feminization of male rat fetuses results in development of a smaller corpus callosum ! 

Could it be then,  I wonder,  that steroid hormones influence the development of the microstructure of the human corpus callosum ?   Or is there anything special about the human corpus callosum as a function of sex -in a manner we have not yet detected ?   If the male sex is more subject to teratogenic callosal aberration,  would the effect occur with any brain stressor during the late fetal period ?  Would this be particularly typical of male-prevalent disorders ? Male-prevalent disorders include fetal alcohol syndrome, fetal malnutrition syndrome,  and several hereditary disorders known to affect fetal brain development in a diffusely unfavorable manner such as dyslexia,  hyperactivity,  Tourette's disease,  and schizophrenia.  There is preliminary evidence to the effect that the corpus callosum does not function normally and/or looks abnormal in hyperactivity, dyslexia, schizophrenia, Gilles de la Tourette disease,  human fetal alcohol syndrome,  and developmental delay due to maternal malnutrition.   I do not believe that the callosal abnormalities are the sole cause, or even the most important cause of any of the above mentioned syndromes.    I do believe however that the corpus callosum deserves study in the context of the developmental neuropsychology of sex differences in each of these specific disorders.   

One example which will help highlight this call for research is alexithymia.   Alexithymia,  as its etymology indicates, consists of an inability to "read" one's emotions.  More specifically in fact,  it consists of a relative inability to give a verbal account of the emotions one is going through at a given time.    If neuropsychology is anything at all, it is the study of hemispheric specialization.  The main specializations of the human hemispheres are verbal specialization of the left hemisphere and emotional and visuospatial specialization of the right hemisphere.   Alexithymia is therefore an extremely interesting condition for neuropsychologists to investigate because while leaving intact one important specialization of each hemisphere (verbalization for the left,  and emotion for the right),  it represents a failure of integration of the two.   This directly leads to the hypothesis that the corpus callosum could,  and perhaps should, be the site of dysfunction in alexithymia.   Indeed,  several investigations have recently shown that this is the case.   When a patient has an epileptic focus in one hemisphere,  an electrical barrage occasionally is triggered from that focus,  jumping across the hemispheres in a cascade leading to a grand mal   attack (generalized convulsions).  When the epilepsy resists most anticonvulsant drugs,  neurosurgeons sometimes cut the corpus callosum (the operation is called a callosotomy) in the hope of constraining the electrical disturbance to the one hemisphere -containing the epileptic focus.   This approach has often been successful in completely preventing grand mal  attacks.    Several investigations have now shown that such patients,  though capable of normal (or very close to normal) emotion and verbal abilities,  have a disproportionate difficulty in expressing,  verbally,  the emotions they are undergoing in emotiogenic (emotionally upheaving) situations.   What does all of this have to do with sex differences, you may ask ?   You already know the answer of course.   Normal boys and men score higher (i.e., are worse) on tests of alexithymia than do normal girls and women.  This finding has been replicated by separate research teams using several different tests of alexithymia,  in different cohorts of normal people.  

A vignette on a case of alexithymia and callosal agenesis

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In 1980, Buchanan, Waterhouse and West published a report of Mr H,  an alexithymic with callosal agenesis (absence of development of the corpus callosum before birth).    This case is particularly revealing because he had no brain abnormalities which are commonly associated with callosal agenesis and he was quite healthy and had a normal IQ.   He was seen at age 37.  He was slightly uncoordinated,    had a reading disability,    and complained of emotional distress and inadequacy.   During one meeting with the authors of the report,  he described the funeral of his only sister in great detail.   During this account,  he wept copiously.  Upon being asked whether remembering the incident was still painful for him he “ looked up quizzically, smiled and then laughingly responded:  I don’t know,  I just can’t explain what I feel. ”   Insistent probing was ineffective in obtaining any emotional label for what he had felt during the account.     As the authors of the report explain,  this condition,  alexithymia,  gives an impression of emotional immaturity and lack of introspection.    Mr  H has little explicit emotionally-laden inner life, is drab,  and even bores himself.   He has always been very dependent on the significant women in his life (mother,  wife).

What little relevant information we have from research on hyperactivity, dyslexia, schizophrenia, Gilles de la Tourette disease,  human fetal alcohol syndrome,  and developmental delay due to maternal malnutrition,  points in the same direction.  These predominantly male disorders seem to be associated with callosal dysfunction and/or abnormality.    Dyslexia is a particularly interesting case in point:   interhemispheric relay and the corpus callosum have been studied in more detail in this disorder.  It makes sense to think of an interhemispheric relay problem in this disorder.  First,  several investigations have found that the corpus callosum is larger in dyslexics than in normals.   Second,  physiological and behavioral investigations have found that interhemispheric relay is faster in dyslexics than normals.  Although I don't wish to get into the technical details of how this is achieved,  I do wish to provide an interpretation of how the callosal dysfunction could contribute to the reading problem of dyslexics.  It seems plausible, though not yet fully proven,  that one of the problems of dyslexics could be that the processing of the written word,  which in normal children is accomplished to a very large extent by the left hemisphere,   is disrupted in dyslexics by concomitant processing occurring in the right hemisphere.  Since post-mortem histology has shown that most developmental dyslexics have cortical ectopias (local abnormalities in tissue composition) in the posterior temporal lobe, more than elsewhere, it would be reasonable to suspect that it is the mid posterior part of the corpus callosum that is the most disturbed in its function.      

Tourette's disease is another very interesting case supporting speculation about a callosal disturbance which could relate to some of the behavioral abnormalities afflicting these patients.   One of the most extraordinary symptoms in psychiatry has got to be the Tourettian coprolalia (filthy language).   Gilles de la Tourette,  a French physician,  was the first to note that there is a recurrence of cases in families,  with multiple changing complex tics, including gestures and vocalizations.  What is extraordinary about this neurological hereditary disorder is that the gestures and vocalizations of the affected children,  as young as eight or nine, may be antisocial or obscene (though most are not).  They are compulsive,  occurring despite the patients' wish to withhold them.    There is much evidence that emotional tone, in particular,  is generated more in the right hemisphere than in the left.  For example,  aprosodia (loss of emotional tone of speech) occurs after right hemisphere lesions,  not left.   However,  speech itself,  except for singing overlearned songs and swearing,  is generated by the left hemisphere.  For example,  a callosotomized patient (a patient who has had his or her corpus callosum surgically severed) is totally unable to name things out loud if they have been seen only in the part of the visual field that feeds the right hemisphere.     Could it be then,  that patients with Gilles de la Tourette's disease are subject to incoercible abnormal activation of the hemispheric centers of spoken language in the left hemisphere (such as Broca's area of the posterior dorsolateral frontal lobe),  themselves throttled by inordinate activation of right hemisphere-generated emotion,  through a defective and unbridled anterior corpus callosum ?   There is not much evidence apt to determine the fate of this idea.   A recent study was the first to investigate gross size of the corpus callosum in Gilles de la Tourette's disease,  using radiological brain imaging.   The corpus callosum had a significantly abnormal morphology.   Unfortunately,  nothing is known at all about interhemispheric relay in this disorder.

Finally,  the most interesting and potentially important example of a disorder suggestive of callosal dysfunction,  is stuttering.   There are two to three times more boy than girl stutterers.   It is well accepted that only the left hemisphere can produce deliberate spontaneous speech (we exclude from this singing, swearing or the like).  Suppose though,  that during speech,  an abnormal influence would come from the motor areas (especially, I think,  an area called the supplementary motor cortex of the frontal lobe) of the other hemisphere,  unbridled ?   This would easily explain why  dysrythmia  of speech (stammering, stuttering, hesitations, etc.) would occur.  A disruptive neural activation from the right hemisphere would interfere with the activities of the left hemisphere during speech.  There is only indirect evidence that this could be the case.   When stutterers are asked to do a different task with each hand,  simultaneously,  it has been repeatedly found that the part of the brain controlling the left hand (the right hemisphere,  probably specifically the supplementary motor cortex) interferes with the part of the brain controlling the right hand (the same area of the left hemisphere).    This is deduced from effects observed in right and left hand performance,  not from observations of the brain itself.   What remains to be done at this point is a magnetic resonance imaging study of the corpus callosum of stutterers and a control group,   and physiological studies of interhemispheric relay.   Interestingly,  some enterprising neurosurgeons have not waited for these studies to start relieving their heavily affected patients by means of callosotomy.   The procedure consists of beaming a high intensity focused magnetic energy force at the corpus callosum. This beam is known to harmlessly inactivate the targeted neurons.  If the patient stops stuttering,  he becomes a reasonable candidate for the surgery.   Table 3 presents details of sex differences in callosal dysfunction.

Table 3

Pediatric neuropsychological syndromes believed to comprise callosal dysfunction and for which the male child is at greater risk and/or is more severely affected

Syndrome	Reference
Head trauma***	Brooks, 1985
Schizophrenia*  **	Szymanski et al, 1995
Dyslexia* **	Geschwind et al, 1985
Tourette’s disease*  **	Hyde et al, 1993
Fetal alcohol syndrome**	Zimmerberg, 1991
Stuttering* **	Andrews et al, 1964
Attention-deficit hyperactivity disorder* **	Szatmari et al, 1989
Alexithymia* **	Saarijarvi, 1993
Prenatal malnutrition**	Galler, 1981
Learning disabilities *  **	Schacter et al, 1987

Note.  A single asterisk indicates a congenital male-prevalent disorder,  a double asterisk indicates a more severe expression of the behavioral disorder,  and a triple asterisk indicates a non congenital disorder involving callosal dysfunction for which the boy is more at risk than the girl.